Our body works a s a system even during complex diseases that is sometimes forgotten. From nutrition to basic immune responses since we are born we start to change how we respond and push the envelope to keep hemostasis in our body.

During this time additional factors also increase or decrease the rate of changes such as life style, environment, inherited as well acquired genetic make-up, types of infections, weight and stress only some of them. As a result we customized our body so deserve a personalized medicine for a treatment. Customized approach is its hype with developing technology to analyze data and compare functional genomics of individuals.

However, still we need the basic cell differentiation to solve the puzzle to respond well and connect the dots for physiological problems. At the stem of the changes there is a cell that respond and amplify its reaction to gain a support to defend at its best . Thus, in this review I like to make a possible connection for pancreatic cancer, obesity-diabetes and innate immune response through natural killer cells.

Pancreatic cancer is one of the most lethal malignancies. Pancreatic cancer is one of the most difficult cancers to treat. Fewer than 5% of patients survive more than 5 years after diagnosis. The 5-year survival rate is despite therapeutic improvements still only 6%. More than 80% of the pancreatic tumors are classified as pancreatic ductal adenocarcinoma (PDA).

When cells in the pancreas that secrete digestive enzymes (acinar cells) turn into duct-like structures, pancreatic cancer can develop. Oncogenic signaling – that which causes the development of tumors – can influence these duct-like cells to form lesions that are a cancer risk.

Crossing roads

The recent publication brought up the necessity to understand how pancreatic cancer and IL17 are connected.

Schematic diagram showing the central role of IL-17B–IL-17RB signaling in pancreatic cancer metastasis.

Simply, obesity and diabetes increases the risks of cancers, cardiovascular disease, hypertension, and type-2 DM. There is a very big public health concern as obesity epidemic, the incidence of diabetes is increasing globally, with an estimated 285 million people, or 6.6% of the population from 20 to 79 years of age, affected this is especially more alarming as child obesity is on the rise.

According to a World Health Organization (WHO) report showing that 400 million people are obese in the world, with a predicted increase to 700 million by 2015 and in the US, 30–35 percent of adults are obese. In addition, high BMI and increased risk of many common cancers, such as liver, endometrium, breast, pancreas, and colorectal cancers have a linear increasing relationship.

The BMI is calculated by dividing body weight in kilograms by height squared in meters kg/m2). The current standard categories of BMI are as follows: underweight, <18.5; normal weight, 18.5–24.9; overweight, 25.0–29.9; obese, 30.0–34.9; and severely obese, > or = 35.0).

Furthermore, natural killer cells not only control innate immune responses but have function in other immune responses that was not recognized well before.

Recently, there have been reports regarding Natural Killer cells on was about the function of IL17 that is produced by iNKT, a subtype of NK, for a possible drug target. In addition, regulation of receptors that are up or downregulated by NK cells for a precise determination between compromised cells and healthy cells.

Therefore, instead of sole reliance on SNPs, or GWAS for early diagnostics or only organ system base pathology, compiling the overall health of the system is necessary for a proper molecular diagnostics and targeted therapies.

What is Pancreas cancer

SNAP SHOT:

Incidence

It is a rare type of cancer.

20K to 200K US cases per year

Medically manageable

Treatment can help

Requires a medical diagnosis

lab tests or imaging

spreads rapidly and has a poor prognosis.

treatments may include: removing the pancreas, radiation, and chemotherapy.

Ages affected; even though person may develop this cancer from age 0 to 60+ there is a high rate of incidence after age 40.

People may experience:

Pain: in the abdomen or middle back

Whole body: nausea, fatigue, or loss of appetite

Also common: yellow skin and eyes, fluid in the abdomen, weight loss, or dark urine

The pancreas secretes enzymes that aid digestion and hormones that help regulate the metabolism of sugars.

The study, published in Nature Communications, suggests that targeting the gene in question – protein kinase D1 (PKD1) – could lead to new ways of halting the development of one of the most difficult tumors to treat.

“As soon as pancreatic cancer develops, it begins to spread, and PKD1 is key to both processes. Given this finding, we are busy developing a PKD1 inhibitor that we can test further,” says the study’s co-lead investigator, Dr. Peter Storz.

Do we have new markers?

Is it possible check the cancer along with glucose levels or insulin at the point of care or companion diagnostics?

Therapy

New Solutions in Therapies

ABRAXANE (paclitaxel formulated as albumin bound nanoparticles; nab-paclitaxel), in combination with gemcitabine, has been recommended for use within NHS Scotland by the Scottish Medicines Consortium (SMC) for the treatment of metastatic adenocarcinoma of the pancreas.

The SMC decision is based on results from the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, published in the October 2013 edition of the New England Journal of Medicine, which demonstrated an increase in median overall survival of 1.8 months when compared to gemcitabine alone [(8.5 months vs. 6.7 months respectively) (HR 0.72; 95% CI 0.62 to 0.83 P<0.001)].

Updated results from post-hoc analysis of the MPACT trial based on an extended data cut-off (8 months) at the time the trial was closed demonstrated an increase in the median overall survival benefit of 2.1 months when compared to gemcitabine alone [(8.7 months vs. 6.6 months respectively) (HR 0.72,95% CI = 0.62 to 0.83, P<.001)].

Targeting stroma is another approached that is followed by TGen to potentially extend patient survival in all cases including advanced cases based on a report at Clinical Cancer Research, published online by the American Association for Cancer Research. Thus this eliminates one of the limiting factor to reach tumor cells and destroying the accumulation of stroma — the supporting connective tissue that includes hyaluronan and few other collagen types.

One of the study leaders, Andrew Biankin, a Cancer Research UK scientist at the University of Glasgow in the UK said that “Being able to identify which patients would benefit from platinum-based treatments would be a game-changing moment for treating pancreatic cancer, potentially improving survival for a group of patients.”

In the journal Nature, the international team- including scientists from Cancer Research UK showed the evidence of large chunks of DNA being shuffled around, which they were able to classify according to the type of disruption they created in chromosomes.

The study concludes there are four subtypes of pancreatic cancer, depending on the frequency, location and types of DNA rearrangement. It terms the subtypes: stable, locally rearranged, scattered and unstable.

Can we develop an immunotherapy?

Genetics of Pancreatic Cancer

There are many ongoing studies to develop diagnostics technologies and treatments. However, the etiology of PC is not well understood. Pancreas has dual functions that include 2% of endocrine hormone secretion and 98% exocrine secretion, enzymes, to help digestion. As a result, pancreatic cancer is related to obesity, overweight, diabetes.

First, eliminating the risk factors can be the simplest path. Next approach is dropping the obesity and diabetes to prevent the occurrence of cancers since in the U.S. population, 50 percent are overweight, 30 percent are medically obese and 10 percent have diabetes mellitus (DM). Tobacco smoking, alcohol consumptions, chronic pancreatitis, and genetic risk factors, have been recognized as potential risk factors for the development and progression of PC.

Many studies showed that the administration of anti-diabetic drugs such as metformin and thiazolidinediones (TZD) class of PPAR-γ agonists decreases the risk of cancers. Thus, these agents are thought to be the target to diagnose or cure PC.

Type 2 diabetes mellitus has been associated with an increased risk of several human cancers, such as liver, pancreatic, endometrial, colorectal, breast, and bladder cancer. The majority of the data show that metformin therapy decreases, while insulin secretagog drugs slightly increase the risk of certain types of cancers in type 2 diabetes.

Metformin can decrease cell proliferation and induce apoptosis in certain cancer cell lines. Endogenous and exogenous (therapy induced) hyperinsulinemia may be mitogenic and may increase the risk of cancer in type 2 diabetes. Type 2 diabetes mellitus accounts for more than 95% of the cases.

In PDA these cells have been reported to express specific genes such as Aldh1 or CD133. To date, more than 20 case-control studies and cohort and nested case-control studies with information on the association between diabetes and pancreatic cancer, BMI and cancer, and obesity and cancer have been reported.

Meta analysis and cohort studies:

Meta studies for Diabetes and PC

Most of the diabetes and PC studies were included in two meta-analyses, in 1995 and in 2005, investigating the risk of pancreatic cancer in relation to diabetes.

The first meta-analysis, conducted in 1995, included 20 of these 40 published case-control and cohort studies and reported an overall estimated relative risk (RR) of pancreatic cancer of 2.1 with a 95% confidence interval (CI) of 1.6-2.8. These values were relatively unchanged when the analyses were restricted to patients who had diabetes for at least 5 years (RR, 2.0 [95% CI, 1.2-3.2]).

The second meta-analysis, which was conducted in 2005, included 17 case-control and 19 cohort and nested case-control studies published from 1996 to 2005 and demonstrated an overall odds ratio (OR) for pancreatic cancer of 1.8 and 95% CI of 1.7-1.9 . Individuals diagnosed with diabetes within 4 years before their pancreatic cancer diagnosis had a 50% greater risk of pancreatic cancer than did those diagnosed with diabetes more than 5 years before their cancer diagnosis (OR, 2.1 [95% CI, 1.9-2.3] versus OR, 1.5 [95% CI, 1.3-1.8]; P = 0.005).

In a recent pooled analysis of 2192 patients with pancreatic cancer and 5113 cancer-free controls in three large case-control studies conducted in the United States (results of two of the three studies were published after 2005),

Risk estimates decreased as the number of years with diabetes increased.

Meta studies in 2003 and 2008 showed a week positive association between BMI and PC. In 2003, a meta-analysis of six case-control and eight prospective studies including 6,391 PC cases 2% increase in risk per 1 kg/m2 increase in BMI. In 2008, 221 datasets, including 282,137 incidence of cancer cases with 3,338,001 subjects the results were similar RR, 1.12; CI, 1.02–1.22.

In 2007, 21 prospective studies handled , 10 were from the United States, 9 were from Europe, and 2 were from Asia and studies was conducted including 3,495,981 individuals and 8,062 PC cases. There was no significant difference between men and women and the estimated summary risk ratio (RR) per 5 kg/m2 increase in BMI was 1.12 (95% CI, 1.06–1.17) in men and women combined.

This study concluded that concluded that there was a positive association between BMI and risk of PC, per a 5 kg/m2 increase in BMI may be equal to a 12% increased risk of PC.

The location and type of the obesity may also signal for a higher risk. The recent Women’s Health Initiative study in the United States among 138,503 postmenopausal showed that women central obesity in relation to PC (n=251) after average of 7.7 years of follow-up duration demonstrated that central adiposity is related to developing PC at a higher risk. Based on their result “women in the highest quintile of waist-to-hip ratio have a 70 percent (95% CI, 10–160%) greater risk of PC compared with women in the lowest quintile”

Age of obesity or being overweight versus risk of developing PC was also examined.

Regardless of their DM status they were at risk and decreased their survival even more so among men than women between age of 14-59.

This association was different between men and women from the ages of 14 to 59:

stronger in men (adjusted OR, 1.80; 95% CI, 1.45–2.23)

weaker in women (adjusted OR, 1.32; 95% CI, 1.02–1.70).

The effect of BMI , obesity and overweight had reduced overall survival of PC regardless of disease stage and tumor resection status

high BMI (= or > 25) 20 to 49 years , an earlier onset of PC by 2 to 6 years.

obese patients: hazard ratio, 1.86, 95% CI, 1.35–2.56).

overweight or obese 30 to 79 years, in the year prior to recruitment

overweight patients: hazard ratio, 1.26, 95% CI, 0.94–1.69;

Similarly, the authors concluded that:

Being overweight or obese during early adulthood was associated with a greater risk of PC and a younger age of disease onset, whereas obesity at an older age was associated with a lower overall survival in patients diagnosed with PC.

More recently, several large prospective cohort studies with a long duration of follow-up has been conducted in the U.S. showing a positive association between high BMI and the risk of PC (adjusted RR 1.13–1.54), suggesting the role of obesity and overweight with higher risk in the development and eventual death due to PC.

Although the role of smoking and gender in the association of obesity and PC is not clear, the new evidence strongly supports a positive association of high BMI with increased risk of PC, consistent with the majority of early findings; however, all recent studies strongly suggest that obesity and overweight are independent risk factor of PC.

Diabetes was associated with a 1.8-fold increase in risk of pancreatic cancer (95% CI, 1.5-2.1).

How pancreatic cancer is related to obesity, overweight, BMI, diabetes

Connections in Physiology and Pathology:

Altogether cumulative data suggest that DM has a three-fold increased risk for the development of PC and a two-fold risk for biliary cancer insulin resistance and abnormal glucose metabolism, even in the absence of diabetes, is associated with increased risk for the development of PC. Obesity alters the metabolism towards insulin resistance through affecting gene expression of inflammatory cytokines, adipose hormones such as adipokines, and PPAR-γ.

Furthermore, adiponectin also pointed out to be a negative link factor for cancers such as colon, breast, and PC. Therefore, insulin resistance is one of the earliest negative effects of obesity, early altered glucose metabolism, chronic inflammation, oxidative stress and decreased levels of adipose hormone adiponectin and PPAR-γ, key regulators for adipogenesis.

Potential pathways directly linking obesity and diabetes to pancreatic cancer. Obesity and diabetes cause mutiple alterations in glucose and lipid hemastasis, microenvironments, and immune responses, which result in the activation of several oncogenic signaling pathways.

aNumber of genes making up the pathway/ number of genes survived the PCA-LRT (P ≤ 0.10).

bNumber of SNPs in the “reconstructed” pathways/number of principal components for LRT.

cP value was estimated by LRT in logistic regression model with adjustment of age, sex, study site, pack years(continuous), obesity or diabetes as appropriate, and five principal components for population structure.

bNumber of genes interacting with a risk factor of interest (P ≤ 0.05) in a given pathway divided by total number of genes making up that pathway.

Pancreatic Cancer and Diabetes:

We conclude that diabetes type II has a fundamental influence on pancreatic ductal adenocarcinoma by stimulating cancer cell proliferation, while metformin inhibits cancer cell proliferation. Chronic inflammation had only a minor effect on the pathophysiology of an established adenocarcinoma.

Diabetes increases tumor size and proliferation of carcinoma cells

Diabetes does not decrease cell death in carcinomas

Diabetes II like syndrome reduces the number of Aldh1+cells within the tumor

Metformin decreases tumor size and proliferation of carcinoma cells

Much is known about factors increasing the likelihood to develop PDA. Identified risk factors include among others chronic pancreatitis, long lasting diabetes, and obesity. Patients with chronic and especially hereditary pancreatitis have a very high relative risk of developing pancreatic cancer of 13.3 and 69.0, respectively. Patients with diabetes and obesity have a moderately increased relative risk of 1.8 and 1.3. These studies indicate that a substantial number of patients with PDA also suffer from local inflammation or diabetes.

Type 2 diabetes mellitus is likely the third modifiable risk factor for pancreatic cancer after cigarette smoking and obesity. The relationship between diabetes and pancreatic cancer is complex. Diabetes or impaired glucose tolerance is present in more than 2/3rd of pancreatic cancer patients.

Epidemiological investigations have found that long-term type 2 diabetes mellitus is associated with a 1.5-fold to 2.0-fold increase in the risk of pancreatic cancer. A causal relationship between diabetes and pancreatic cancer is also supported by findings from prediagnostic evaluations of glucose and insulin levels in prospective studies.

Insulin resistance and associated hyperglycemia, hyperinsulinemia, and inflammation have been suggested to be the underlying mechanisms contributing to development of diabetes-associated pancreatic cancer.

“ They reported a nearly seven-fold higher prevalence of diabetes in pancreatic cancer patients compared to controls (47% vs. 7%). In a retrospective study using similar criteria, Chari et al. found the prevalence of diabetes in pancreatic cancer patients to be 40%. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932318/”

Natural Killer cells usually placed under non-specific immune response as a first defend mechanism during innate immunity. NKs responses to innate immune reactions but not only viruses but also bacteria and parasitic infections develop a new line of defense. These reactions involve amplification of many cytokines based on the specific infection or condition. Thus, these activities help NKs to evolve.

However, their functions proven to be more than innate immune response since from keeping the pregnancy term to prevent recurrent abortions to complex diseases such as cancer, diabetes and cardiovascular conditions they have roles thorough awakening chemokines and engaging them specifically with their receptors to activate other immune cells. For example, there is a signaling mechanism connection between NKs and DCs to respond attacks. Furthermore, there are interactions between various types of immune cells and they are specific for example between NK and Tregs.

During pregnancy there is a special kind of interaction between NK cells and Tregs.

There can be several reasons such as to protect pregnancy from the immunosuppressive environment so then the successful implantation of the embryo and tolerance of the mother to the embryo can be established. In normal pregnancy, these cells are not killers, but rather provide a microenvironment that is pregnancy compatible and supports healthy placentation.

During cancer development tumors want to build a microenvironment through an array of highly orchestrated immune elements to generate a new environment against the host. In normal pregnancy, decidua, the uterine endometrium, is critical for the development of placental vasculature.

This is the region gets thicks and thin during female cycles to prevent or accept pregnancies. As a result, mother nature created that 70% of all human decidual lymphocytes are NK cells, defined as uterine or decidual NK (dNK) cells.

The NK cell of decidua (dNK) and peripheral blood NK cells are different since dNK cells are characterized as CD56brightCD16−CD3−, express killer cell immunoglobulin-like receptors and exhibit low killing capacity despite the presence of cytolytic granules, and a higher frequency of CD4+CD25bright

The lesson learn here is that pregnancy and mammary tissue are great examples of controlling cellular differentiation and growth since after pregnancy all these cells go back to normal state.

Understanding these minute differences and relations to manipulate gene expression may help to:

Develop better biomaterials to design long lasting medical devices and to deliver vaccines without side effects.

Generate safer vaccines as NKcells are the secret weapons in DC vaccination and studying their behavior together with T-cell activation in vaccinated individuals might predict clinical outcome.

Establish immunotherapies based on interactions between NK cells and Tregs for complex diseases not only cancer, but also many more such as autoimmune disorder, transplants, cardiovascular, diabetes.

Trascription factors are the silence players of the gene expression that matches input to output as a cellular response either good or bad but this can be monitored and corrected with a proper meical device or diagnostics tool to provide successful treatment regimen.

Therefore, the effects of Tregs on NK during gene regulation analyzed and compared among other living organisms for concerved as well as signature sequence targets even though the study is on human.

Unfortunatelly we can’t mutate the human for experimental purposes so comparative developmental studies now its widely called stem cell biology with a system biology approach may help to establish the pathway.

NK and T reg regulation share a common interest called T box proteins. These proteins are conserved and also play role in development of heart at very early development, embryology. What is shared among all T-box is simply lie behind the capacity for DNA binding through the T-box domain and transcriptional regulatory activity, which plays a role in controlling the expression of developmental gene in all animal species.

The Special T box protein: T-bet

The first identified T-box protein was Brachyury (T). in a nut shell

The T-box domain is made up of about 180 amino-acid residues that includes a specific sequence of DNA

called T-box domain, TCACACCT between residues 135 and 326 in mouse.

However, T-bet which is the T-box protein expressed in T cells and also called as TBX21 is quite conserved in 18 members of the T-box protein (TBX) family

since it has a crucial dual role during development and for coordination of both innate and adaptive immune responses.

T-Bet was originally cloned for its role in Th1 lineage, it has a role in Th2 development, too.

The whole mechanism based on direct activation and modulation mechanisms in that T-Bet directly activates IFN-γ gene transcription and enhances development of Th1 cells at the same time modulates IL-2 and Th2 cytokines in an IFN-γ-independent manner that creates an attenuation of Th2 cell development.

Thus, certain lipids ligands or markers can be utilized during vaccine design to steer the responses for immune therapies against autoimmune diseases. As a result, tumors can be removed and defeated by manipulating NKs action.

INKT:

NKT has functions in diabetes, asthma. One cell type that has been proposed to contribute immensely to the development of asthma is NKT cells, which constitute a small population of lymphocytes that express markers of both T cells (T-cell receptor, TCR) and NK cells (e.g., NK1.1, NKG2D). NKT cells can be subdivided into at least three subtypes, based on their TCR. Type I NKT cells or invariant NKT (iNKT) cells express invariant TCR chains (V14–J18 in mice and V24–J18 in humans) coupled with a limited repertoire of V chains (V8, V7 and V2 in mice and V11 in humans).

The studies in the past decade showed the protective mechanism of NKT cells during the development of Type 1 diabetes can be complex.

First, NKT cells can impair the differentiation of anti-islet reactive T cells into Th1 effector cells in a cell–cell contact dependent manner, which did not require Th2 cytokine production or CD1d recognition.

Last, anergic iNKT cells induced by protracted αGalCer stimulation can induce the production of noninflammatory DCs, which inhibit diabetes development in an Ag-specific fashion.

These findings point to an important protective role for NKT cells during autoimmune pathogenesis in the pancreas.

A crucial role has been suggested for invariant natural killer T cells (iNKT) in regulating the development of asthma, a complex and heterogeneous disease characterized by airway inflammation and airway hyperreactivity (AHR).

iNKT cells constitute a unique subset of T cells responding to endogenous and exogenous lipid antigens, rapidly secreting a large amount of cytokines, which amplify both innate and adaptive immunity.

IL17:

Terashima A et al (2008) identified a novel subset of natural killer T (NKT) cells that expresses the interleukin 17 receptor B (IL-17RB) for IL-25 (also known as IL-17E) and is essential for the induction of Airway hypersensitive reaction (AHR). IL-17RB is preferentially expressed on a fraction of CD4(+) NKT cells but not on other splenic leukocyte populations tested.

They strongly suggested that IL-17RB(+) CD4(+) NKT cells play a crucial role in the pathogenesis of asthma.

NKT connection can be established between through targeting IL17 and IL17RB. There is a functional specialization of interleukin-17 family members. Interleukin-17A (IL-17A) is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17 has six family members (IL-17A to IL-17F).

Although IL-17A and IL-17F share the highest amino acid sequence homology, they perform distinct functions; IL-17A is involved in the development of autoimmunity, inflammation, and tumors, and also plays important roles in the host defenses against bacterial and fungal infections, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses.

There is no one easy answer for the role of IL-17 in pancreatic cancer as there are a number of unresolved issues and but it can be only suggested that pro-tumorigenic IL-17 activity is confined to specific subsets of patients with pancreatic cancer since there is a increased expression of IL-17RB in these patients about ∼40% of pancreatic cancers presented on their histochemical staining (IHC- immunohistochemistry.

IL17 and breast cancer:

In addition, during breast cancer there is an increased signaling of interleukin-17 receptor B (IL-17RB) and IL-17B. They promoted tumor formation in breast cancer cells in vivo and even created acinus formation in immortalized normal mammary epithelial cells in vitro cell culture assays.

Furthermore, the elevated expression of IL-17RB not only present itself stronger than HER2 for a better prognosis but also brings the shortest survival rate if patients have increased IL-17RB and HER2 levels.

However, decreased level of IL-17RB in trastuzumab-resistant breast cancer cells significantly reduced their tumor growth. This may prompt a different independent role for IL-17RB and HER2 in breast cancer development.

These results suggest that the amplified IL-17RB/IL-17B signaling pathways may serve as a therapeutic target for developing treatment to manage IL-17RB-associated breast cancer.

IL 17 and Asthma:

A requirement for iNKT cells has also been shown in a model of asthma induced with air pollution, ozone and induced with respiratory viruses chronic asthma studied in detail. In these studies specific types of NKT cells found to that specific types of NK and receptors trigger of asthma symptoms. Taken together, these studies indicate that both Th2 cells (necessary for allergen-specific responses) and iNKT cells producing IL-4 and IL-13 are required for the development of allergen-induced AHR.

Although CD4+ IL-4/IL-13-producing iNKT cells (in concert with antigen-specific Th2 cells) are crucial in allergen-induced AHR, NK1.1–IL-17-producing iNKT cells have a major role in ozone-induced AHR.

A main question in iNKT cell biology involves the identification of lipid antigens that can activate iNKT cells since this allow to identify which microorganisms to attack as a result, the list of microorganisms that produce lipids that activate iNKT cells is rapidly growing.

Chemokines have a crucial role in organogenesis of various organs including lymph nodes, arising from their key roles in stem cell migration. Moreover, most homeostatic chemokines can control the movement of lymphocytes and dendritic cells and eventually adaptive immunity. Chemokines are heparin-binding proteins with 4 cysteine residues in the conserved positions.

The human chemokine system has about 48 chemokines. They are subgrouped based on:

functionally classified as inflammatory, homeostatic, or both, based on their expression patterns

Chemokines are structurally divided into 4 subgroups :CXC, CC, CX3C, and C. X represent an aminoacid so the first 2 cysteines are separated by 1 is grouped as CXC and 3 amino acids is called CX3C chemokines but in CC the first 2 cysteines are adjacent. In the C chemokines there is no second and fourth cysteines.

Various types of inflammatory stimuli induce abundantly the expression of inflammatory chemokines to induce the infiltration of inflammatory cells such as granulocytes and monocytes/macrophages.

inflammatory chemokines are CXC chemokines with ELR motif and CCL2.

homeostatic chemokines are expressed constitutively in specific tissues or cells.

Chemokines exert their biological activities by binding their corresponding receptors, which belong to G-protein coupled receptor (GPCR) with 7-span transmembrane portions. Thus, the target cell specificity of each chemokine is determined by the expression pattern of its cognate receptor .

Moreover, chemokines can bind to proteoglycans and glycosaminoglycans with a high avidity, because the carboxyl-terminal region is capable of binding heparin.

Consequently, most chemokines are produced as secretory proteins, but upon their secretion, they are immobilized on endothelium cells and/or in extracellular matrix by interacting with proteoglycans and glycosaminoglycans. The immobilization facilitates the generation of a concentration gradient, which is important for inducing the target cells to migrate in a directed way.

In conclusion, having to develop precise early diagnostics is about determining the overlapping genes as key among diabetes, obesity, overweight and pancreas functions even pregnancy can be suggested.

It seems feasible to develop an immunotherapy for pancreatic cancer with the focus on chemokines and primary signaling between iNKT and Tregs such as one of the recent plausable target IL-17 and IL17 RB.

Johansen D et al Metabolic factors and the risk of pancreatic cancer: a prospective analysis of almost 580,000 men and women in the Metabolic Syndrome and Cancer Project. Cancer Epidemiol Biomarkers Prev. 2010;19:2307–2317.

Cancer Research UK. Statistics and outlook for pancreatic cancer. Available athttp://www.cancerresearchuk.org/about-cancer/type/pancreatic-cancer/treatment/statistics-and-outlook-for-pancreatic-cancer Accessed February 2015

Fang, M. et al. CD94 is essential for NK cell-mediated resistance to a lethal viral disease.Immunity34, 579–589 (2011).This study using CD94-deficient mice shows that the activating receptor formed by CD94 and NKG2E is essential for the resistance of C57BL/6 mice to mousepox.

I will make the connections and like to check out Oncology and Clinical Trials Global. I usually look at http://www.clinicaltrials.gov
I can include novel immuotherapies as an introduction.

My main concept is to make a point to use Natural Killer cells in junction with Treg specially. This paper differ from other papers by making the connection and translating the original clinical issue to a basic science for developing diagnostics and molecular therapies.

I did research and selected biomarkers and possible approaches to develop the assay that I hesitated to share for IP purposes.
Thank you for your comments!